tbuckley/cabot-search huggingface dataset:
ADAMTS7-Mediated Complement Factor H Degradation Potentiates Complement Activation to Contributing to Renal Injuries
Authors: Zihan Ma, Chenfeng Mao, Yiting Jia, Fang Yu, Ping Xu, Ying Tan, Qing-Hua Zou, Xu-Jie Zhou, Wei Kong, Yi Fu
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Complement factor H (CFH) dysfunction by an incomplete underlying mechanism causes various complement-mediated renal injuries. We identified metalloprotease ADAMTS7 as a novel binding protein of CFH that further degrades CFH and potentiates complement activation. ADAMTS7 deficiency alleviated CFH degradation and renal pathologies in lupus nephritis and renal ischemia-reperfusion injury in mice, but without affecting complement-dependent bactericidal activity. The investigation revealed a novel mechanism to explain CFH dysfunction in complement-mediated renal injuries. ADAMTS7 would be a promising target for anticomplement therapies that would potentially avoid increased risk of infection, which is the drawback of current strategies. Background The dysfunction of complement factor H (CFH), the main soluble complement negative regulator, potentiates various complement-induced renal injuries. However, insights into the underlying mechanism of CFH dysfunction remain limited. In this study, we investigated whether extracellular protease-mediated degradation accounts for CFH dysfunction in complement-mediated renal injuries. Methods An unbiased interactome of lupus mice kidneys identified CFH-binding protease. In vitro cleavage assay clarified CFH degradation. Pristane-induced SLE or renal ischemia-reperfusion (I/R) injury models were used in wild-type and ADAMTS7 −/− mice. Results We identified the metalloprotease ADAMTS7 as a CFH-binding protein in lupus kidneys. Moreover, the upregulation of ADAMTS7 correlated with CFH reduction in both lupus mice and patients. Mechanistically, ADAMTS7 is directly bound to CFH complement control protein (CCP) 1–4 domain and degraded CCP 1–7 domain through multiple cleavages. In mice with lupus nephritis or renal I/R injury, ADAMTS7 deficiency alleviated complement activation and related renal pathologies, but without affecting complement-mediated bactericidal activity. Adeno-associated virus–mediated CFH silencing compromised these protective effects of ADAMTS7 knockout against complement-mediated renal injuries in vivo . Conclusion ADAMTS7-mediated CFH degradation potentiates complement activation and related renal injuries. ADAMTS7 would be a promising anticomplement therapeutic target that does not increase bacterial infection risk.
Genetic and Physiological Effects of Insulin-Like Growth Factor-1 (IGF-1) on Human Urate Homeostasis
Authors: Asim K. Mandal, Megan P. Leask, Nicholas A. Sumpter, Hyon K. Choi, Tony R. Merriman, David B. Mount
Journal: Journal of the American Society of Nephrology (2023)

Background Metabolic syndrome and hyperinsulinemia are associated with hyperuricemia. Insulin infusion in healthy volunteers elevates serum urate (SU) by activating net urate reabsorption in the renal proximal tubule, whereas insulin-like growth factor-1 (IGF-1) infusion reduces SU by mechanisms unknown. Variation within the IGF1R gene also affects SU levels. Methods Colocalization analyses of a SU genome-wide association studies signal at IGF1R and expression quantitative trait loci signals in cis using COLOC2, RT-PCR, Western blotting, and urate transport assays in transfected HEK 293T cells and in Xenopus laevis oocytes. Results Genetic association at IGF1R with SU is stronger in women and is mediated by control of IGF1R expression. Inheritance of the urate-lowering homozygous genotype at the SLC2A9 locus is associated with a differential effect of IGF1R genotype between men and women. IGF-1, through IGF-1R, stimulated urate uptake in human renal proximal tubule epithelial cells and transfected HEK 293T cells, through activation of IRS1, PI3/Akt, MEK/ERK, and p38 MAPK; urate uptake was inhibited in the presence of uricosuric drugs, specific inhibitors of protein tyrosine kinase, PI3 kinase (PI3K), ERK, and p38 MAPK. In X. laevis oocytes expressing ten individual urate transporters, IGF-1 through endogenous IGF-1R stimulated urate transport mediated by GLUT9, OAT1, OAT3, ABCG2, and ABCC4 and inhibited insulin's stimulatory action on GLUT9a and OAT3. IGF-1 significantly activated Akt and ERK. Specific inhibitors of PI3K, ERK, and PKC significantly affected IGF-1 stimulation of urate transport in oocytes. Conclusions The combined results of infusion, genetics, and transport experiments suggest that IGF-1 reduces SU by activating urate secretory transporters and inhibiting insulin's action.
Catalyzing Advocacy and Policies for Patients with Kidney Disease
Authors: Josephine P. Briggs, Thomas Hostetter, Neil R. Powe
Journal: Journal of the American Society of Nephrology (2023)

1Journal of the American Society of Nephrology, Bernard, Maine 2University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 3Department of Medicine, University of California San Francisco at the Priscilla Chan and Mark Zuckerberg San Francisco General Hospital, San Francisco, California Correspondence: Josephine P. Briggs, PO Box 126, Bernard, ME 04612. Email: [email protected]
Hypoxia-Inducible Factor 2α Attenuates Renal Ischemia-Reperfusion Injury by Suppressing CD36-Mediated Lipid Accumulation in Dendritic Cells in a Mouse Model
Authors: Junwen Qu, Dawei Li, Jingsi Jin, Nan Sun, Jiajin Wu, Chao Yang, Lingling Wu, Shaoyong Zhuang, Haoyu Wu, Ruoyang Chen, Yaofei Ren, Chen Zhong, Liang Ying, Yan Zhang, Xiaodong Yuan, Ming Zhang
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Hypoxia is a hallmark of renal ischemia-reperfusion injury (IRI) and serves as an essential regulator of innate immune responses during this process, although the mechanisms of this regulation remain unclear. Here, we showed in a murine model that HIF-2 α knockout in dendritic cells (DCs) exacerbated renal IRI through activation of natural killer T cells. Mechanistically, HIF-2 α deficiency upregulated CD36 expression of DCs, leading to cellular lipid accumulation. Pharmacologic inhibition of CD36 in DCs resulted in renoprotection by reducing lipid content and suppressing natural killer T cell activation. Our study strongly suggests that targeting the HIF-2 α /CD36 regulatory axis may be a strategy for alleviating renal IRI. Background Hypoxia and hypoxia-inducible factors (HIFs) play essential and multiple roles in renal ischemia-reperfusion injury (IRI). Dendritic cells (DCs) comprise a major subpopulation of the immunocytes in the kidney and are key initiators and effectors of the innate immune responses after IRI. The role of HIF-2 α in DCs remains unclear in the context of renal IRI. Methods To investigate the importance of HIF-2 α in DCs upon renal IRI, we examined the effects of DC-specific HIF-2 α ablation in a murine model. Bone marrow–derived DCs (BMDCs) from DC-specific HIF-2 α –ablated mice and wild-type mice were used for functional studies and transcriptional profiling. Results DC-specific ablation of HIF-2 α led to hyperactivation of natural killer T (NKT) cells, ultimately exacerbating murine renal IRI. HIF-2 α deficiency in DCs triggered IFN- γ and IL-4 production in NKT cells, along with upregulation of type I IFN and chemokine responses that were critical for NKT cell activation. Mechanistically, loss of HIF-2 α in DCs promoted their expression of CD36, a scavenger receptor for lipid uptake, increasing cellular lipid accumulation. Furthermore, HIF-2 α bound directly to a reverse hypoxia-responsive element (rHRE) in the CD36 promoter. Importantly, CD36 blockade by sulfo- N -succinimidyl oleate (SSO) reduced NKT cell activation and abolished the exacerbation of renal IRI elicited by HIF-2 α knockout. Conclusions Our study reveals a previously unrecognized role of the HIF-2 α /CD36 regulatory axis in rewiring DC lipid metabolism under IRI-associated hypoxia. These findings suggest a potential therapeutic target to resolve long-standing obstacles in treatment of this severe complication.
Changes in the prevalence of infectious diseases before and after the COVID-19 pandemic in Pakistan
Authors: Muhammad Suleman Rana, Muhammad Usman, Muhammad Masroor Alam, Muhammad Tahir, Aamer Ikram, Syed Sohail Zahoor Zaidi, Muqarrab Kashif, Umair Massab, Rani Faryal, Muhammad Anas, Nadeem Ullah, Muhammad Salman
Journal: Journal of Infection (2023)
IL1RA mediated the effects of aspirin on COVID-19 severity: A Mendelian randomization study
Authors: Xuxu Liu, Zhenyi Lv, Qiang Wang, Jingjing Yu, Jing Wang, You Zhou, Meijuan Sui, Chenjun Hao, Dongbo Xue, Yingmei Zhang
Journal: Journal of Infection (2023)
Characteristics and risk factors of prolonged viable virus shedding in immunocompromised patients with COVID-19: a prospective cohort study
Authors: Sung-Woon Kang, Jun-Won Kim, Ji Yeun Kim, So Yun Lim, Choi-Young Jang, Euijin Chang, Jeong-Sun Yang, Kyung-Chang Kim, Hee-Chang Jang, Dasol Kim, Younmin Shin, Joo-Yeon Lee, Sung-Han Kim
Journal: Journal of Infection (2023)
Thiol oxidative stress-dependent degradation of transglutaminase2 via protein S-glutathionylation sensitizes 5-fluorouracil therapy in 5-fluorouracil-resistant colorectal cancer cells
Authors: Xia Li, Yan Ma, Junzhou Wu, Maowei Ni, Aiping Chen, Yun Zhou, Wumin Dai, Zhongjian Chen, Ruibin Jiang, Yutian Ling, Qinghua Yao, Wei Chen
Journal: Drug Resistance Updates (2023)

5-Fluorouracil (5-Fu) is a first-line drug for colorectal cancer (CRC) therapy. However, the development of 5-Fu resistance limits its chemotherapeutic effectiveness and often leads to poor prognoses of CRC. Transglutaminase 2 (TGM2), a member of the transglutaminase family, is considered to be associated with chemoresistance through apoptotic prevention in various cancers including CRC. TGM2 was found to be overexpressed in two 5-Fu-resistant CRC cell lines and down-regulated by increased thiol oxidative stress induced by inhibition of glutathione reductase (GR). The present study aimed to explore the role of TGM2 in 5-Fu-resistant CRC and the mechanism of action by which the elevated thiol oxidative stress down-regulates TGM2 protein level. The results revealed that 5-Fu-resistance induced by overexpression of TGM2 in CRC cells was reversed through up-regulation of thiol oxidative stress. Knockdown of TGM2 increased the chemosensitivity of CRC cells to 5-Fu. Thiol oxidative stress potentially enhanced the therapeutic effect of 5-Fu in the resistant CRC cells by promotion of 5-Fu-induced apoptosis through down-regulation of TGM2. The elevated thiol oxidative stress increased the S-glutathionylation of TGM2 and led to proteasomal degradation of TGM2. Furthermore, Cys193 was identified as the S-glutathionylation site in TGM2, and its mutation resulted in thiol oxidative stress-mediated CRC cell apoptotic resistance. TGM2-induced EMT was also suppressed by the elevated thiol oxidative stress. A xenograft tumor model confirmed the effect of thiol oxidative stress in the reversal of 5-Fu resistance in CRC cells in vivo. TGM2 protein expression level was found to be significantly higher in human CRC specimens than in non-cancerous colorectal tissues. Taken together, the present data suggest an important role of TGM2 in 5-Fu resistance in CRC cells. Up-regulation of thiol oxidative stress could be a potential therapeutic approach for treating 5-Fu-resistant CRC and TGM2 may serve as a potential therapeutic target of thiol oxidative stress.
Tuning the corona-core ratio of polyplex micelles for selective oligonucleotide delivery to hepatocytes or hepatic immune cells
Authors: WanLing Foo, Zoltán Cseresnyés, Carsten Rössel, Yingfeng Teng, Anuradha Ramoji, Mingzhe Chi, Walter Hauswald, Sophie Huschke, Stephanie Hoeppener, Jürgen Popp, Felix H. Schacher, Marek Sierka, Marc Thilo Figge, Adrian T. Press, Michael Bauer
Journal: Biomaterials (2023)

Targeted delivery of oligonucleotides or small molecular drugs to hepatocytes, the liver's parenchymal cells, is challenging without targeting moiety due to the highly efficient mononuclear phagocyte system (MPS) of the liver. The MPS comprises Kupffer cells and specialized sinusoidal endothelial cells, efficiently clearing nanocarriers regardless of their size and surface properties. Physiologically, this non-parenchymal shield protects hepatocytes; however, these local barriers must be overcome for drug delivery. Nanocarrier structural properties strongly influence tissue penetration, in vivo pharmacokinetics, and biodistribution profile. Here we demonstrate the in vivo biodistribution of polyplex micelles formed by polyion complexation of short interfering (si)RNA with modified poly(ethylene glycol)-block-poly(allyl glycidyl ether) (PEG-b-PAGE) diblock copolymer that carries amino moieties in the side chain. The ratio between PEG corona and siRNA complexed PAGE core of polyplex micelles was chemically varied by altering the degree of polymerization of PAGE. Applying Raman-spectroscopy and dynamic in silico modeling on the polyplex micelles, we determined the corona-core ratio (CCR) and visualized the possible micellar structure with varying CCR. The results for this model system reveal that polyplex micelles with higher CCR, i.e., better PEG coverage, exclusively accumulate and thus allow passive cell-type-specific targeting towards hepatocytes, overcoming the macrophage-rich reticuloendothelial barrier of the liver.
Vaccination against SARS-CoV-2 in pregnancy during the Omicron wave: the prospective cohort study of the Italian obstetric surveillance system
Authors: Edoardo Corsi Decenti, Michele Antonio Salvatore, Donatella Mandolini, Serena Donati, Irene Alberi, Franco Camandona, Paola Casucci, Irene Cetin, Andrea Ciavattini, Fabrizio Damiani, Francesca Di Sebastiano, Lorenza Driul, Fiorenza Droghini, Giuseppe Ettore, Daniele Farsetti, Massimo Piergiuseppe Franchi, Livio Leo, Marco Liberati, Lucia Li Sacchi, Mariavittoria Locci, Claudio Martini, Gianpaolo Maso, Federico Mecacci, Alessandra Meloni, Anna Domenica Mignuoli, Luisa Mondo, Danila Morano, Rocco Paradiso, Enrica Perrone, Roberta Piccinno, Federico Prefumo, Luca Ramenghi, Morena Rocca, Letizia Sampaolo, Sabrina Scalchi, Sergio Crescenzo Antonio Schettini, Daniela Simeone, Serena Simeone, Martin Steinkasserer, Fabrizio Taddei, Marina Tesorone, Vito Trojano, Caterina Tronci, Micaela Veneziano, Antonella Vimercati
Journal: Clinical Microbiology and Infection (2023)
Lineages of language and the diagnosis of asthma
Authors: G. Netuveli, B. Hurwitz, A. Sheikh
Journal: Journal of the Royal Society of Medicine (2006)

Asthma, wheeze and cough are words with profoundly differing histories, etymologies and meanings. Yet their medical usage today is clustered around the diagnosis and management of a single disease. Hitherto, asthma has been a clinical diagnosis but wheeze, cough and asthma now are key terms in cross-cultural questionnaire surveys which seek information on asthma prevalence. In this essay, we examine differences in the linguistic properties of terms likely to be relevant to interpreting large-scale variations in asthma prevalence uncovered by questionnaires. We show how etymologically distinct each term is: while asthma and cough each share semantic congruencies across six European languages, albeit for different reasons, there is less congruence across these languages for the term wheeze. The medical meanings of all three terms contrast with meanings revealed by the non-medical usage of all three terms, which are highly figurative. Linguistic considerations indicate that interpretation of international questionnaires that phrase questions in terms of cough, asthma and their derivatives are likely to be more reliable for the purposes of comparing prevalence than those which deploy questions phrased in terms of wheeze.
Patient-Controlled Analgesia
Authors: Robert K. Parker
Journal: JAMA (1991)

<h3>Objective.</h3> —To assess the influence of a continuous (basal) morphine infusion as part of a patient-controlled analgesia (PCA) system on the postoperative analgesic requirement and on recovery parameters following abdominal hysterectomy. <h3>Design.</h3> —Single-center, randomized, controlled protocol. <h3>Setting.</h3> —University medical center. <h3>Participants.</h3> —A total of 230 adult women were randomly assigned to receive no morphine infusion (control group) or a continuous 0.5-, 1.0-, or 2.0-mg/h morphine infusion. Each patient was able to self-administer supplemental intravenous bolus doses of morphine (1 to 2 mg) using a PCA infuser. <h3>Main Outcome Measures.</h3> —Use of the PCA device, opioid-related side effects, recovery times, and the patients' assessment of pain and sedation on linear visual analog scales were recorded during the 72-hour study period. Follow-up questionnaires were completed by the patients and their health care professionals to assess the overall adequacy of PCA therapy. <h3>Results.</h3> —Patients who received the 2-mg/h morphine infusions received significantly more opioid medication 9 to 72 hours after their operation than those who received no infusion (control group). The presence of a continuous morphine infusion of 0.5 to 2 mg/h did not significantly decrease the number of patient demands or supplemental bolus doses administered compared with the control group. Overall, 168 (84%) of the 199 patients who completed the 72-hour study were able to achieve adequate analgesia without requiring changes in the PCA regimen or experiencing major side effects. Recovery times and outcome variables were similar in all four groups. <h3>Conclusion.</h3> —The routine use of a continuous opioid infusion in combination with a standard PCA regimen does not improve pain management compared with PCA alone after abdominal hysterectomy. (<i>JAMA</i>. 1991;266:1947-1952)
Trends in Surgical Revascularization for Renal Artery Disease
Authors: Andrew C. Novick
Journal: JAMA (1987)

We reviewed our experience with surgical revascularization (SR) for renal artery disease (RAD) in 361 patients from 1975 through 1984 to illustrate the evolving role of SR in the management of these patients. The time intervals selected for comparison were 1975 through 1980 (n=174) and 1981 through 1984 (n=187). Since 1981, in patients with atherosclerosis, SR has been done more often in elderly patients (30% vs 10.4%), in patients with generalized atherosclerosis (87% vs 73%), and for the sole purpose of preserving renal function (36% vs 14%). Since 1981, fewer patients with atherosclerosis have undergone SR solely to treat renovascular hypertension (26% vs 41%). Since 1981, in patients with fibrous dysplasia, SR has been done in more patients with branch renal artery disease (70% vs 28%). These trends in the performance of SR have been due to the advent of percutaneous transluminal angioplasty as effective therapy for certain patients, improved results of SR in elderly patients with atherosclerosis, an enhanced appreciation of advanced atherosclerotic RAD as a correctable cause of renal failure, and the development of more effective techniques for SR in patients with severe aortic atherosclerosis and branch RAD. The overall clinical results of SR remain excellent in properly selected patients with RAD. (<i>JAMA</i>1987;257:498-501)
Elective Cyclosporine Withdrawal After Renal Transplantation
Authors: Bertram L. Kasiske
Journal: JAMA (1993)

<h3>Objective.</h3> —To determine whether it is safe to electively discontinue cyclosporine therapy after renal transplantation. <h3>Data Source.</h3> —MEDLINE and bibliographies from recent publications. <h3>Study Selection.</h3> —Controlled trials assessing the rate of acute rejection, graft loss, and mortality after elective cyclosporine withdrawal. <h3>Data Extraction.</h3> —We compared outcomes in patients who underwent withdrawal from cyclosporine treatment with patients who were not withdrawn (part 1), and in a separate analysis (part 2), with patients who never received cyclosporine. <h3>Data Synthesis.</h3> —In part 1 of the meta-analysis, consisting of 10 randomized and seven nonrandomized trials, there was a greater combined rate of acute rejection among patients in whom cyclosporine was withdrawn compared with control patients who continued to receive cyclosporine (weighted difference in episodes per patient, 126; 95% confidence interval [Cl], 0.085 to 0.167;<i>P</i>&lt;.001). However, there were no differences in graft loss (weighted difference in grafts lost per patient per year, —0.009; 95% Cl, —0.022 to 0.004;<i>P</i>=0.19) or mortality (weighted difference in deaths per patient per year, —0.005; 95% Cl, —0.016 to 0.006;<i>P</i>=.40) attributable to cyclosporine withdrawal. In part 2 of the meta-analysis, consisting of three randomized and three nonrandomized trials, the combined rate of graft loss for patients who were withdrawn from cyclosporine was not significantly different vs control patients who never received cyclosporine (weighted difference in grafts lost per patient per year, —0.020; 95% Cl, —0.043 to 0.003;<i>P</i>=.08). However, when the three randomized trials were analyzed separately, graft survival was better in patients who were withdrawn from cyclosporine (weighted difference in grafts lost per patient per year, 0.0382; 95% Cl, 0.0002 to 0.0762;<i>P</i>=.049). None of the outcomes was affected by the timing or manner of the cyclosporine withdrawal. <h3>Conclusions.</h3> —The increased incidence of acute rejection following elective cyclosporine withdrawal does not affect short-term graft or patient survival after renal transplantation. Whether long-term consequences will outweigh the benefits of elective withdrawal remains to be determined. (<i>JAMA</i>. 1993;269:395-400)
Epidural and Subarachnoid Anesthesia
Authors: Richard J. Ward
Journal: JAMA (1965)

Effects of a high subarachnoid block and high epidural block, with and without epinephrine in the anesthetic solution, were studied in the same patients. High subarachnoid block produces hypotension, decreased stroke volume, decreased cardiac output, and a slight decrease in peripheral resistance. High epidural block with epinephrine in the anesthetic solution produces the same degree of hypotension, but an increase in heart rate, stroke volume, and cardiac output and a marked drop in peripheral resistance. High epidural block without epinephrine produces changes similar to, but not as profound as, subarachnoid anesthesia. Unmedicated patients blocked by high subarachnoid anesthesia are able to hyperventilate and maintain normal blood gas tensions.